研究人员发现，来自结核分枝杆菌的已知蛋白磷酸酶PtpB是一种抑制宿主炎症小体-焦亡途径的磷脂磷酸酶。从机制上讲，PtpB使宿主细胞膜上的磷脂酰肌醇-4-单磷酸酯和磷脂酰肌醇-(4,5)-双磷酸酯去磷酸化，从而破坏了切割的gasdermin D（GSDMD）的膜定位，抑制了细胞因子的释放和巨噬细胞的焦亡。
值得注意的是，这种磷酸酶活性需要PtpB与泛素结合。破坏磷脂磷酸酶活性或PtpB的泛素相互作用模体，可增强宿主GSDMD依赖的免疫反应，并减少细胞内病原体的生存。因此，病原体通过改变宿主的膜组成来抑制焦亡作用并抵消宿主的免疫力。
据介绍，炎症小体介导的GSDMD切割会引起焦亡和炎症细胞因子的释放，从而控制病原体感染，但病原体如何逃避这种免疫反应在很大程度上仍未被探索。
附：英文原文
Title: A bacterial phospholipid phosphatase inhibits host pyroptosis by hijacking ubiquitin
Author: Qiyao Chai, Shanshan Yu, Yanzhao Zhong, Zhe Lu, Changgen Qiu, Yang Yu, Xinwen Zhang, Yong Zhang, Zehui Lei, Lihua Qiang, Bing-Xi Li, Yu Pang, Xiao-Bo Qiu, Jing Wang, Cui Hua Liu
Issue&Volume: 2022-10-14
Abstract: The inflammasome-mediated cleavage of gasdermin D (GSDMD) causes pyroptosis and inflammatory cytokine release to control pathogen infection, but how pathogens evade this immune response remains largely unexplored. Here we identify the known protein phosphatase PtpB from Mycobacterium tuberculosis as a phospholipid phosphatase inhibiting the host inflammasome-pyroptosis pathway. Mechanistically, PtpB dephosphorylated phosphatidylinositol-4-monophosphate and phosphatidylinositol-(4,5)-bisphosphate in host cell membrane, thus disrupting the membrane localization of the cleaved GSDMD to inhibit cytokine release and pyroptosis of macrophages. Notably, this phosphatase activity requires PtpB binding to ubiquitin. Disrupting phospholipid phosphatase activity or the ubiquitin-interacting motif of PtpB enhanced host GSDMD-dependent immune responses and reduced intracellular pathogen survival. Thus, pathogens inhibit pyroptosis and counteract host immunity by altering host membrane composition.
DOI: abq0132
Source: https://www.science.org/doi/10.1126/science.abq0132